The long-term objective of my proposed research project is the identification of genes contributing to schizophrenia susceptibility. I propose a novel approach based on the hypothesis that a subset of patients with schizophrenia harbor subtle but detectable DnA copy number alterations (deletions or duplications) leading to aberrant function of a schizophrenia susceptibility gene or genes within the altered region. I will take advantage of new technologies allowing for rapid and sensitive identification of cryptic copy number alterations in individual genomes. I will use array-based Comparative Genomic Hybridization (aCGH) to screen for such alterations in a well-characterized set of 80 schizophrenia probands. I will confirm identified alterations and characterize the deleted or duplicated regions. I will also design assays to screen for the specific genomic alterations in family members of probands using methods such as quantitative PCR and PCR across breakpoint junctions. In my third specific aim, I will sequence exons and regulatory regions of genes within the altered genomic regions in a set of 32 additional schizophrenia probands. Array CGH hybridizations will be carried out by collaborators at the Roswell Park Cancer Institute. I will perform array data analysis and followup experiments in the rich environment of Johns Hopkins Hospital, under mentors Drs. R. Margolis, C. Ross (experts in neuropsychiatry) and D. Valle (expert in human genetics and molecular biology). I will concurrently participate in a series of courses to gain expertise in array analysis and to develop a solid grounding in bioinformatics, genomics, population genetics, psychiatry, and neuroscience. This training, in combination with my extensive experience in molecular biology and human genetics, will allow me to emerge as a full-fledged independent investigator and leader in the field of molecular genetics of major mental illness. [unreadable] [unreadable] Relevance: This project should lead to the identification of genes containing mutations which are associated with susceptibility to schizophrenia, a major health problem in the USA and worldwide, with a universal prevalence of approximately 1%. Currently there are no treatments that completely alleviate symptoms, and most drugs in use have serious side effects. Understanding the genetic factors underlying schizophrenia should lead to the development of more specific and effective treatments. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]